Simulation study of individual cellular responses by bystander effects in cellular population

放射線誘発バイスタンダー効果による個々の細胞応答のシミュレーション研究

服部 佑哉; 横谷 明徳; 渡辺 立子

Hattori, Yuya; Yokoya, Akinari; Watanabe, Ritsuko

放射線が照射された細胞から、同じ細胞集団内の放射線が当たっていない細胞へ、細胞間シグナル伝達によって放射線の影響が伝達することが知られている。本研究では、個々の細胞応答と細胞間シグナル伝達を考慮した細胞集団の放射線応答モデルを用いて、集団内の細胞に対する放射線と細胞間シグナル伝達の作用を調べた。本研究で用いる放射線応答モデルは、細胞集団を2次元平面の格子の集団で表現し、1格子を1細胞とした。格子ごとに、(1)細胞への放射線照射、(2)放射線誘発の細胞間シグナル伝達、(3)放射線と細胞間シグナルに誘発されたDNA損傷、(4)DNA損傷による細胞周期変調と細胞死を記述した。まず、モデルの動作確認のため、モデルの計算データと実験データを比較した。シミュレーション空間に細胞集団を設置し、細胞集団全体に放射線を照射した。照射後に生存細胞をカウントした結果、実験データと同様に、生存率の線量依存性が確認できた。細胞集団中央の1細胞にのみ放射線を照射するシミュレーションでも、生存細胞数は、実験データと同程度であった。また、モデルが示した個々の細胞の細胞周期を調べたところ、細胞間シグナル伝達によって細胞周期が変調する細胞が増加することが確認できた。発表では、放射線誘発の細胞間シグナル伝達による細胞の生存率と細胞周期変調への影響について報告する。

When only a limited number of cells in a population are hit by radiation, non-irradiated cells might receive from the irradiated cells intercellular signals that induce biological effects known as "bystander effects". To understand the responses of each cell in the inhomogeneous population, we have developed a mathematical model of intercellular signaling and individual cellular responses, particularly focusing on cell cycle progression, cell cycle arrest, and cell death. In our model, the cellular population was described by grids. Each grid represented each cell. We assumed that absorbed dose was given in each grid (cell). The intercellular-signals emitted from the cells were assumed to be transferred through culture medium and gap junctions, and their concentrations in each grid were calculated based on a diffusion equation. We assumed that individual cell have targets which are necessary to progress the cell cycle. Both irradiation and the intercellular signals were assumed to inactivate "targets" in the cell. The number of inactivated targets decides cellular state, cell cycle progression, cell cycle arrest or cell death. The cell cycle was described as a virtual clock with cyclic stages (G1, S, G2, M phases) and several check-points. In the condition of normal cell-cycle progression and proliferation, our model successfully reproduced growth curves of experimental data previously reported for non-irradiated cellular population. When we irradiated one cell in the center of cellular population, some of non-irradiated cells caused inactivation of the targets by the intercellular signals, resulting in cell cycle arrest and cell death. Based on the simulation and analysis of the temporal and spatial dynamics of intercellular signaling, inactivated targets, cell cycle arrest and cell death, we will discuss the mechanism of radiation-induced responses in inhomogeneous cellular populations.